Aqueous liquid preparation containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid

ABSTRACT

An aqueous liquid preparation of the present invention containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid or its pharmacologically acceptable salt or a hydrate thereof, an alkyl aryl polyether alcohol type polymer such as tyloxapol, or a polyethylene glycol fatty acid ester such as polyethylene glycol monostearate is stable. Since even in the case where a preservative is incorporated into said aqueous liquid preparation, the preservative exhibits a sufficient preservative effect for a long time, said aqueous liquid preparation in the form of an eye drop is useful for the treatment of blepharitis, conjunctivitis, scleritis, and postoperative inflammation. Also, the aqueous liquid preparation of the present invention in the form of a nasal drop is useful for the treatment of allergic rhinitis and inflammatory rhinitis (e.g. chronic rhinitis, hypertrophic rhinitis, nasal polyp, etc.).

This is a divisional of Ser. No. 13/353,653 filed Jan. 19, 2012, whichis a divisional of Ser. No. 10/525,006, filed Mar. 28, 2005, now issuedas U.S. Pat. No. 8,129,431, which is a U.S. national stage ofInternational Application No. PCT/JP2004/000350 filed Jan. 16, 2004.

TECHNICAL FIELD

The present invention relates to an aqueous liquid preparationcontaining 2-amino-3-(4-bromobenzoyl)phenylacetic acid or apharmacologically acceptable salt thereof or a hydrate thereof. Moreparticularly, the present invention relates to an aqueous liquidpreparation containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid or apharmacologically acceptable salt thereof or a hydrate thereof and analkyl aryl polyether alcohol type polymer or a polyethylene glycol fattyacid ester.

BACKGROUND ART

Benzoylphenylacetic acid derivatives including bromfenac (generic name)of formula (I):

of which chemical name is 2-amino-3-(4-bromobenzoyl)phenylacetic acidare known as disclosed in JP-A-23052/1977 and its corresponding U.S.Pat. No. 4,045,576. 2-Amino-3-(4-bromobenzoyl)phenylacetic acid, itspharmacologically acceptable salt and a hydrate thereof are known as anon-steroidal anti-inflammatory agent, and they are effective againstinflammatory diseases of anterior or posterior segment of the eye, suchas blepharitis, conjunctivitis, scleritis, and postoperativeinflammation in the field of ophthalmology, and its sodium salt has beenpractically used in the form of eye drops (“New Drugs in Japan, 2001”,2001 Edition, Published by Yakuji Nippo Ltd., May 11, 2001, p. 27-29).

The eye drop as mentioned above is designed to stabilize2-amino-3-(4-bromobenzoyl)phenylacetic acid by means of addition of awater-soluble polymer (e.g. polyvinylpyrrolidone, polyvinyl alcohol,etc.) and a sulfite (e.g. sodium sulfite, potassium sulfite, etc.)(Japanese patent No. 2,683,676 and its corresponding U.S. Pat. No.4,910,225).

In addition, as an eye drop other than the above-mentioned one, Japanesepatent No. 2,954,356 (corresponding to U.S. Pat. Nos. 5,603,929 and5,653,972) discloses a stable ophthalmic composition which comprisesincorporating an antibacterial quaternary ammonium polymer and boricacid into an acidic ophthalmic agent. The acidic agent described thereinincludes, for example, 2-amino-3-(4-bromobenzoyl)phenylacetic acid.

Further, in Japanese patent No. 2,954,356, there is the followingdescription-“Benzalkonium chloride is a widely used preservative inophthalmic solutions. However, benzalkonium chloride and otherquaternary ammonium compounds are generally considered to beincompatible with ophthalmic compositions of drugs with acidic groups,such as nonsteroidal anti-inflammatory drugs. These preservatives losetheir ability to function as they form complexes with the charged drugcompounds”.

In these prior art references, there is no disclosure that alkyl arylpolyether alcohol type polymers or polyethylene glycol fatty acid estersare able to stabilize an aqueous liquid preparation of2-amino-3-(4-bromobenzoyl)phenylacetic acid or its pharmacologicallyacceptable salt, and inhibit decrease in preservative effect ofbenzalkonium chloride and other quaternary ammonium compounds.

DISCLOSURE OF THE INVENTION

It is an object of the present invention to provide an aqueous liquidpreparation comprising 2-amino-3-(4-bromobenzoyl)phenylacetic acid or apharmacologically acceptable salt thereof or a hydrate thereof, which isstable within a pH range giving no irritation to eyes and in which, whena preservative such as benzalkonium chloride is incorporated therein,preservative effect of the preservative does not substantiallydeteriorate.

Another object of the invention is to provide a method for stabilizingan aqueous liquid preparation of 2-amino-3-(4-bromobenzoyl)phenylaceticacid or a pharmacologically acceptable salt thereof or a hydratethereof.

Further object of the invention is to provide an aqueous liquidpreparation comprising 2-amino-3-(4-bromobenzoyl)phenylacetic acid or apharmacologically acceptable salt thereof or a hydrate thereof and apreservative, wherein, when specifically a quaternary ammonium salt suchas benzalkonium chloride is incorporated as a preservative, decrease inpreservative effect of said preservative is inhibited.

As a result of various studies, the inventors of the present inventionhave found that, by adding, for example, an alkyl aryl polyether alcoholtype polymer such as tyloxapol, or a polyethylene glycol fatty acidester such as polyethylene glycol monostearate to an aqueous liquidpreparation of 2-amino-3-(4-bromobenzoyl)phenylacetic acid or apharmacologically acceptable salt thereof or a hydrate thereof, theaqueous solution becomes stable within a pH range giving no irritationto eyes, and change of the 2-amino-3-(4-bromobenzoyl)phenylacetic acidover time can be inhibited, and furthermore, when the aqueous solutioncontains a preservative, deterioration in the preservative effect ofsaid preservative can be inhibited for a long period of time. Theinventors of the present invention have further studied extensively andcompleted the present invention.

Namely, the present invention relates to:

(1) An aqueous liquid preparation comprising2-amino-3-(4-bromobenzoyl)phenylacetic acid or a pharmacologicallyacceptable salt thereof or a hydrate thereof, and an alkyl arylpolyether alcohol type polymer or a polyethylene glycol fatty acidester,

(2) The aqueous liquid preparation according to the above (1), whereinthe alkyl aryl polyether alcohol type polymer has a polymerizationdegree of 3 to 10, the alkyl contains 1 to 18 carbon atoms, the aryl isa phenyl residue, and the polyether alcohol is represented by theformula O(CH₂CH₂O)_(x)H in which X is an integer of 5 to 100,(3) The aqueous liquid preparation according to the above (1) or (2),wherein the alkyl aryl polyether alcohol type polymer is tyloxapol,(4) The aqueous liquid preparation according to the above (1), whereinthe carbon number of the fatty acid in the polyethylene glycol fattyacid ester is 12 to 18,(5) The aqueous liquid preparation according to the above (1) or (4),wherein the polyethylene glycol fatty acid ester is polyethylene glycolmonostearate,(6) The aqueous liquid preparation according to any one of the above (1)to (3), wherein the concentration of the alkyl aryl polyether alcoholtype polymer is selected from a range of minimum concentration of 0.01w/v % to maximum concentration of 0.5 w/v %,(7) The aqueous liquid preparation according to any one of the above(1), (2) or (4), wherein the concentration of the polyethylene glycolfatty acid ester is selected from a range of minimum concentration of0.02 w/v % to maximum concentration of 0.1 w/v %,(8) The aqueous liquid preparation according to any one of the above (1)to (7), wherein the concentration of the2-amino-3-(4-bromobenzoyl)phenylacetic acid or a pharmacologicallyacceptable salt thereof or a hydrate thereof is 0.01 to 0.5 w/v %,(9) The aqueous liquid preparation according to any one of the above (1)to (8), wherein benzalkonium chloride is contained as a preservative,(10) The aqueous liquid preparation according to anyone of the above (1)to (9), wherein the pharmacologically acceptable salt of2-amino-3-(4-bromobenzoyl)phenylacetic acid is a sodium salt,(11) The aqueous liquid preparation according to any one of the above(1) to (10), wherein the pH of the aqueous liquid preparation is withina range of 7 to 9,(12) The aqueous liquid preparation according to the above (11), whereinthe pH of the aqueous liquid preparation is within a range of 7.5 to8.5,(13) The aqueous liquid preparation according to any one of the above(1) to (12), wherein the aqueous liquid preparation is an eye drop,(14) The aqueous liquid preparation according to any one of the above(1) to (12), wherein the aqueous liquid preparation is a nasal drop,(15) An eye drop comprising sodium2-amino-3-(4-bromobenzoyl)phenylacetate hydrate and 0.01 to 0.5 w/v % oftyloxapol,(16) An eye drop comprising sodium2-amino-3-(4-bromobenzoyl)phenylacetate hydrate and 0.02 to 0.1 w/v % ofpolyethylene glycol monostearate,(17) A method for stabilizing 2-amino-3-(4-bromobenzoyl)phenylaceticacid or a pharmacologically acceptable salt thereof or a hydrate thereofin an aqueous liquid preparation, which comprises incorporatingtyloxapol or polyethylene glycol monostearate into an aqueous liquidpreparation containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid or apharmacologically acceptable salt thereof or a hydrate thereof, and(18) A method for inhibiting decrease in preservative effect of apreservative in an aqueous liquid preparation of2-amino-3-(4-bromobenzoyl)phenylacetic acid or a pharmacologicallyacceptable salt thereof or a hydrate thereof, which comprisesincorporating tyloxapol or polyethylene glycol monostearate into anaqueous liquid preparation containing2-amino-3-(4-bromobenzoyl)phenylacetic acid or a pharmacologicallyacceptable salt thereof or a hydrate thereof and a preservative.

According to the present invention, a stable aqueous liquid preparationcontaining 2-amino-3-(4-bromobenzoyl)phenylacetic acid or apharmacologically acceptable salt thereof or a hydrate thereof can beprepared by incorporating an alkyl aryl polyether alcohol type polymersuch as tyloxapol, or a polyethylene glycol fatty acid ester such aspolyethylene glycol monostearate into an aqueous liquid preparationcontaining 2-amino-3-(4-bromobenzoyl)phenylacetic acid or apharmacologically acceptable salt thereof or a hydrate thereof. Also, anaqueous liquid preparation of the present invention, wherein apreservative is incorporated, has a sufficient preservative effect.

Therefore, the aqueous liquid preparation of the present invention isadvantageously used as an eye drop for the treatment of, for example,blepharitis, conjunctivitis, scleritis, and postoperative inflammation.In addition, such aqueous liquid preparation can be used as a nasal dropfor the treatment of, for example, allergic rhinitis and inflammatoryrhinitis (e.g. chronic rhinitis, hypertrophic rhinitis, nasal polyp,etc.).

The pharmacologically acceptable salt of2-amino-3-(4-bromobenzoyl)phenylacetic acid includes, for example, analkali metal salt such as sodium salt and potassium salt, and analkaline earth metal salt such as calcium salt and magnesium salt, amongwhich sodium salt is especially preferable.

2-Amino-3-(4-bromobenzoyl)phenylacetic acid and its pharmacologicallyacceptable salt can be prepared according to the method as described inJP-A-23052/1977 (corresponding to U.S. Pat. No. 4,045,576) or by asimilar method thereof. These compounds can be obtained as their hydratedepending on synthetic conditions and recrystallization conditions. Thehydrate includes 1/2 hydrate, 1 hydrate, and 3/2 hydrate, among which3/2 hydrate is preferable.

In the aqueous liquid preparation of the present invention, the content(concentration range) of 2-amino-3-(4-bromobenzoyl)phenylacetic acid ora pharmacologically acceptable salt thereof or a hydrate thereof isusually about 0.01 to 0.5 w/v %, preferably about 0.05 to 0.2 w/v %,especially about 0.1 w/v %, and it is preferable to appropriately varythe content depending on the purpose of use and the degree of disease tobe treated.

The carbon number of the alkyl in the an alkyl aryl polyether alcoholtype polymer which is a non-ionic surfactant used as a stabilizer for2-amino-3-(4-bromobenzoyl)phenylacetic acid or a pharmacologicallyacceptable salt thereof or a hydrate thereof is approximately 1 to 18.Specifically, the alkyl group includes, for example, methyl, ethyl,propyl, isopropyl, cyclopropyl, butyl, isobutyl, sec-butyl, tert-butyl,cyclobutyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-ethylpropyl,4-methylpentyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 1,2-dimethylbutyl,2-ethylbutyl, cyclopentyl, hexyl, cyclohexyl, heptyl, isoheptyl, octyl,isooctyl, nonyl, isononyl, decyl, isodecyl, undecyl, isoundecyl,dodecyl, isododecyl, tridecyl, isotridecyl, tetradecyl, isotetradecyl,pentadecyl, isopentadecyl, hexadecyl, isohexadecyl, heptadecyl,isoheptadecyl, octadecyl, isooctadecyl, and isomers thereof, among whichoctyl and its isomer (e.g. isooctyl, sec-octyl, 1-methylheptyl,1-ethylhexyl, 2-ethylhexyl, 1-propylpentyl, 1,5-dimethylhexyl,1,1,3,3-tetramethylbutyl, etc.) are preferable, and1,1,3,3-tetramethylbutyl which is an isomer of octyl groups isespecially preferable.

The aryl in the alkyl aryl polyether alcohol type polymer can bepreferably a phenyl residue. The polyether alcohol can be represented bythe formula O(CH₂CH₂O)_(x)H in which X is an integer of 5 to 100,preferably 5 to 30, more preferably 8 to 10. The average polymerizationdegree is preferably about 3 to 10.

Among the above-mentioned alkyl aryl polyether alcohol type polymers,tyloxapol having the following formula is especially preferable.

The fatty acid of the polyethylene glycol fatty acid ester which is anon-ionic surfactant used as a stabilizer for2-amino-3-(4-bromobenzoyl)phenylacetic acid or a pharmacologicallyacceptable salt thereof or a hydrate thereof can be preferably a fattyacid having the carbon number of 12 to 18. Specific examples of suchpolyethylene glycol fatty acid esters are polyethylene glycolmonostearate (e.g. polyoxyl 8 stearate, polyoxyl 40 stearate, etc.),polyethylene glycol monolaurate, polyethylene glycol monooleate,polyethylene glycol diisostearate, polyethylene glycol dilaurate,polyethylene glycol dioleate, and the like. Among these compounds,polyethylene glycol monostearate is preferable, and polyoxyl 40 stearateis especially preferable. The polyoxyl 40 stearate is a monostearic acidester of an ethylene oxide condensed polymer, and can be represented bythe formula C₁₇H₃₅COO(CH₂CH₂O)_(n)H which is a non-ionic surfactant andn is about 40.

Although the content (concentration range) of the alkyl aryl polyetheralcohol type polymer in the aqueous liquid preparation of the presentinvention depends on the kind of compounds used, the minimumconcentration is about 0.01 w/v % and the maximum concentration is about0.5 w/v %. With respect to the tyloxapol content (concentration range),for example, the minimum content is about 0.01 w/v %, 0.02 w/v % or 0.03w/v %, and the mamximum content is about 0.05 w/v %, 0.1 w/v %, 0.3 w/v% or 0.5% w/v, and preferably the minimum content is about 0.02 w/v %and the maximum content is about 0.05 w/v %.

Although the content (concentration range) of the polyethylene glycolfatty acid ester in the aqueous liquid preparation of the presentinvention depends on the kind of compounds used, it is within a range ofabout 0.02 w/v % of minimum concentration to about 0.1 w/v % of maximumconcentration. For example, the content (concentration range) ofpolyethylene glycol monostearate is within a range of about 0.02 w/v %of minimum content to about 0.1 w/v % of maximum content, and preferablywithin a range of about 0.02 w/v % of the minimum content to about 0.05w/v % of the maximum content.

The incorporation ratio of tyloxapol in the aqueous liquid preparationof the invention is within a range of the minimum content of about 0.1or 0.2 part by weight to the maximum content of about 0.5, 1, 3 or 5parts by weight, relative to 1 part by weight of2-amino-3-(4-bromobenzoyl)phenylacetic acid or its pharmacologicallyacceptable salt or a hydrate thereof.

The incorporation ratio of polyethylene glycol monostearate in theaqueous liquid preparation of the present invention is within a range ofthe minimum content of about 0.2 part by weight to the maximum contentof about 0.5 or 1 part by weight, relative to 1 part by weight of2-amino-3-(4-bromobenzoyl)phenylacetic acid or its pharmacologicallyacceptable salt or a hydrate thereof.

The preservative used in the present invention includes, for example,quaternary ammonium salts (e.g. benzalkonium chloride, benzethoniumchloride, etc.), chlorhexidine gluconate, and the like, among whichbenzalkonium chloride is especially preferable.

Further, so long as the purpose of the present invention is achieved,conventional various additives such as isotonics, buffers, thickners,stabilizers, chelating agents, pH controlling agents, perfumes and thelike may be appropriately added to the aqueous liquid preparation of thepresent invention. The isotonics include sodium chloride, potassiumchloride, glycerine, mannitol, sorbitol, boric acid, glucose, propyleneglycol and the like. The buffers include, for example, phosphate buffer,borate buffer, citrate buffer, tartarate buffer, acetate buffer, boricacid, borax, amino acids, and the like. The thickners includepolyvinylpyrrolidone, carboxymethylcellulose, carboxypropylcellulose,hydroxyethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose, polyvinyl alcohol, sodium polyacrylate,and the like. The stabilizers include sulfites such as sodium sulfiteand the like. The chelating agents include sodium edetate, sodiumcitrate, condensed sodium phosphate and the like. The pH controllingagents include hydrochloric acid, sodium hydroxide, phosphoric acid,acetic acid and the like. The perfumes include 1-menthol, borneol,camphor, Eucalyptus oil, and the like.

With respect to the concentrations of the above various additives in theaqueous liquid preparation of the present invention,

the isotonic is incorporated into an osmotic pressure ratio of about 0.8to 1.2, and the concentrations of the buffer and the thickner to beadded are about 0.01 to 2 w/v % and 0.1 to 10 w/v %, respectively.

The pH of the aqueous liquid preparation of the present invention isadjusted to about 6 to 9, preferably about 7 to 9, especially about 7.5to 8.5.

So long as the purpose of the present invention is achieved, other sameor different kind of active ingredients may be appropriately added.

The aqueous liquid preparation of the present invention can be preparedby per se known method or according to the method as described in theJapanese Pharmacopoeia, 14^(th) Edition, General Rules for Preparations,Solutions or Ophthalmic solutions.

The aqueous liquid preparation of the present invention can be appliedto warm-blooded animals such as human, rat, mouse, rabbit, cow, pig,dog, cat, and the like.

The aqueous liquid preparation of the present invention can be preparedeasily by dissolving the above-mentioned components in, for example,distilled water or sterile purified water. For example, the aqueousliquid preparation in the form of an eye drop can be used for thetreatment of inflammatory diseases in anterior or posterior segment ofthe eye such as blepharitis, conjunctivitis, scleritis, postoperativeinflammation, and the like. The dose of the aqueous liquid preparationcontaining 0.1 w/v % of sodium 2-amino-3-(4-bromobenzoyl)phenylacetatehydrate is, for example, administered to an adult 3 to 6 times daily inan amount of 1 to 2 drops per one time. Depending on the degree ofdiseases, frequency of dosing is appropriately controlled.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention is illustrated by way of the followingExperimental Examples and Working Examples, but it is not restricted bythese Examples.

Experimental Example 1 Stability Test of Sodium2-amino-3-(4-bromobenzoyl)phenylacetate

Four eye drops of sodium 2-amino-3-(4-bromobenzoyl)phenylacetatecomprising the components as shown in Table 1 were prepared, filledrespectively into a polypropylene container and subjected to stabilitytest at 60° C.

TABLE 1 Comparison Component Example 1 A-01 A-02 A-03 Sodium2-amino-3-(4-  0.1 g  0.1 g  0.1 g  0.1 g bromobenzoyl) phenylacetateBoric acid  1.5 g  1.5 g  1.5 g  1.5 g Benzalkonium chloride 0.005 g0.005 g 0.005 g 0.005 g Polysorbate 80  0.15 g — — — Polyoxyl 40stearate —  0.15 g — — Tyloxapol — —  0.15 g  0.02 g Sterile purifiedwater q.s. q.s. q.s. q.s Total volume   100 mL   100 mL   100 mL   100mL pH  7.0  7.0  7.0  7.0 Remaining rate (%) at 51.3 63.7 73.8 89.6 60°C. after 4 weeks

The remaining rate (%) in the above Table 1 indicates values obtained bycorrecting moisture vaporization from the container. As is apparent fromthe Table 1, stability test was carried out under the conditions of pH7.0 at 60° C. for 4 weeks, and sodium2-amino-3-(4-bromobenzoyl)phenylacetate in each eye drop was stable inthe order of tyloxapol-containing preparation>polyoxyl 40stearate-containing preparation>polysorbate 80-containing preparation.

Further, with respect to eye drops containing tyloxapol (compositionsA-02 and A-03), sodium 2-amino-3-(4-bromobenzoyl)phenylacetate incomposition A-03 containing 0.02 w/v % of tyloxapol is more stable thanthat in composition A-02 containing 0.15 w/v % of tyloxapol.

Experimental Example 2 Stability Test of Sodium2-amino-3-(4-bromobenzoyl)phenylacetate

Five eye drops of sodium 2-amino-3-(4-bromobenzoyl)phenylacetatecomprising the components as shown in Table 2 were prepared, filledrespectively into a polypropylene container and preserved at 60° C. for4 weeks, and then the content of 2-amino-3-(4-bromobenzoyl)phenylaceticacid and the pH in each eye drop were measured.

TABLE 2 Components A-04 A-05 A-06 A-07 A-08 Sodium 2-amino-3-(4-  0.1 g 0.1 g  0.1 g  0.1 g  0.1 g bromobenzoyl)phenyl- acetate Boric acid  1.1g  1.1 g  1.1 g  1.1 g  1.1 g Borax  1.1 g  1.1 g  1.1 g  1.1 g  1.1 gBenzalkonium chloride 0.005 g 0.005 g 0.005 g 0.005 g 0.005 gPolysorbate 80 — — — — — Tyloxapol  0.02 g  0.05 g  0.03 g — — Polyoxyl40 stearate — — —  0.02 g  0.05 g Polyvinyl-  2.0 g  2.0 g  2.0 g  2.0 g 1.0 g pyrrolidone (K-30) Sodium edetate  0.02 g  0.02 g  0.02 g  0.02 g 0.02 g Sodium hydroxide q.s. q.s. q.s. q.s. q.s. Sterile purified q.s.q.s. q.s. q.s. q.s. water Total volume   100 mL   100 mL   100 mL   100mL   100 mL pH  8.17  8.16  8.15  8.19  8.19 60° C., Remaining 92.6 90.992.0 93.4 93.1 4 weeks rate (%) pH  8.15  8.16  8.15  8.13  8.14

Table 2 shows the remaining rate and the pH of sodium2-amino-3-(4-bromobenzoyl)phenylacetate after storage at 60° C. for 4weeks, when the remaining rate of sodium2-amino-3-(4-bromobenzoyl)phenylacetate at the time of production of eyedrops is set to 100%. The remaining rate is a value obtained bycorrecting moisture vaporization from the container. As is apparent fromTable 2, the remaining rate of sodium2-amino-3-(4-bromobenzoyl)phenylacetate in the compositions A-04, A-05,A-06, A-07 and A-08 containing 0.02 w/v %, 0.03 w/v % and 0.05 w/v % oftyloxapol or 0.02 w/v % and 0.05 w/v % of polyoxyl 40 stearate is notless than 90% after storage at 60° C. for 4 weeks, which indicates thatthose compositions have sufficient stability for eye drops.

Experimental Example 3 Preservative Effect Test of Aqueous LiquidPreparation Containing Sodium 2-amino-3-(4-bromobenzoyl)phenylacetate

Preservative effect test of compositions A-04, A-05 and A-07 ofExperimental Example 2 was carried out against Staphylococcus aureus(hereinafter referred to as S. aureus), Escherichia Coli (hereinafterreferred to as E. coli), Pseudomonas aeruginosa (hereinafter referred toas P. aeruginosa), Candida albicans (hereinafter referred to as C.albicans) and Aspergillus niger (hereinafter referred to as A. niger).

The results are shown in Tables 3-1, 3-2 and 3-3.

TABLE 3-1 Cell count (CFU/mL) 6 hours 24 hours 7 days 14 days 21 days 28days Inoculum after after after after after after A-04 count inoculationinoculation inoculation inoculation inoculation inoculation S. aureus2.1 × 10⁶ 3.0 × 10¹ 0 0 0 0 0 E. coli 6.5 × 10⁶ 0 0 0 0 0 0 P.aeruginosa 5.8 × 10⁶ 0 0 0 0 0 0 C. albicans 3.2 × 10⁵ — — 0 0 0 0 A.niger 1.8 × 10⁵ — — 0 0 0 0

TABLE 3-2 Cell count (CFU/mL) 6 hours 24 hours 7 days 14 days 21 days 28days Inoculum after after after after after after A-05 count inoculationinoculation inoculation inoculation inoculation inoculation S. aureus2.1 × 10⁶ 1.7 × 10⁵ 2.0 × 10¹ 0 0 0 0 E. coli 6.5 × 10⁶ 0 0 0 0 0 0 P.aeruginosa 5.8 × 10⁶ 0 0 0 0 0 0 C. albicans 3.2 × 10⁵ — — 0 0 0 0 A.niger 1.8 × 10⁵ — — 0 0 0 0

TABLE 3-3 Cell count (CFU/mL) 6 hours 24 hours 7 days 14 days 21 days 28days Inoculum after after after after after after A-07 count inoculationinoculation inoculation inoculation inoculation inoculation S. aureus2.7 × 10⁶ 3.1 × 10⁴ 0 0 0 0 0 E. coli 7.4 × 10⁶ 0 0 0 0 0 0 P.aeruginosa 8.8 × 10⁶ 0 0 0 0 0 0 C. albicans 4.6 × 10⁵ — — 0 0 0 0 A.niger 1.0 × 10⁵ — — 0 0 0 0

As is apparent from Tables 3-1, 3-2 and 3-3, the preservative effect ofcomposition A-04 was found to be compatible with EP-criteria A inEuropean Pharmacopoeia (EP), and those of compositions A-05 and A-07were found to be compatible with EP-criteria B.

The EP-criteria A and EP-criteria B are given in the following.

EP-Criteria A:

Viable cell counts of bacteria (S. aureus, P. aeruginosa) 6 hours, 24hours, and 28 days after inoculation decrease to not more than 1/100,not more than 1/1000, and undetectable, respectively.

Viable cell count of fungi (C. albicans, A. niger) 7 hours afterinoculation decreases to not more than 1/100, and thereafter, the cellcount levels off or decreases.

EP-Criteria B

Viable cell counts of bacteria (S. aureus, P. aeruginosa) 24 hours and 7days after inoculation decrease to not more than 1/10 and not more than1/1000, respectively, and thereafter, the cell count levels off ordecreases.

Viable cell count of fungi (C. albicans, A. niger) 14 days afterinoculation decreases to not more than 1/10, and thereafter, the cellcount keeps the same level as that of 14 days after inoculation.

Example 1 Eye Drop

Sodium 2-amino-3-(4- 0.1 g bromobenzoyl)phenylacetate 3/2 hydrate Boricacid 1.1 g Borax 1.1 g Benzalkonium chloride 0.005 g  Tyloxapol 0.02 g Polyvinylpyrrolidone (K-30) 2.0 g Sodium edetate 0.02 g  Sodiumhydroxide q.s. Sterile purified water to make total volume of 100 mL pH8.17

An eye drop is prepared using the above components in a conventionalmanner.

Example 2 Eye Drop

Sodium 2-amino-3-(4- 0.1 g bromobenzoyl)phenylacetate 3/2 hydrate Boricacid 1.1 g Borax 1.1 g Benzalkonium chloride 0.005 g  Tyloxapol 0.05 g Polyvinylpyrrolidone (K-30) 2.0 g Sodium edetate 0.02 g  Sodiumhydroxide q.s. Sterile purified water to make total volume of 100 mL pH8.16

An eye drop is prepared using the above components in a conventionalmanner.

Example 3 Eye Drop

Sodium 2-amino-3-(4- 0.1 g bromobenzoyl)phenylacetate 3/2 hydrate Boricacid 1.1 g Borax 1.1 g Benzalkonium chloride 0.005 g  Polyoxyl 40stearate 0.02 g  Polyvinylpyrrolidone (K-30) 2.0 g Sodium edetate 0.02g  Sodium hydroxide q.s. Sterile purified water to make total volume of100 mL pH 8.19

An eye drop is prepared using the above components in a conventionalmanner.

INDUSTRIAL APPLICABILITY

The aqueous liquid preparation of the present invention in the form ofeye drops is useful for the treatment of blepharitis, conjunctivitis,scleritis, and postoperative inflammation. Such preparation is alsouseful for the treatment of nasal drop for treatment of, for example,allergic rhinitis and inflammatory rhinitis (e.g. chronic rhinitis,hypertrophic rhinitis, nasal polyp, etc.)

The present application is based on application No. 12427/2003 filed inJapan, and includes the entire contents thereof. By reference, thereferences including patents and patent applications cited herein areincorporated in the present application at the same level as when theentire contents thereof are disclosed. Furthermore, since it is obviousthat the present invention can be carried out beyond the description ofthe above explanation and Working Examples, in light of the foregoingdescription, various other modifications and changes can be made to thepresent invention, and thus these modifications and changes should beconsidered to be within the scope of the claims appended hereto.

The invention claimed is:
 1. A stable aqueous liquid preparationcomprising: (a) a first component; and (b) a second component; whereinthe first component is 2-amino-3-(4-bromobenzoyl)phenylacetic acid or apharmacologically acceptable salt thereof or a hydrate thereof, whereinthe hydrate is at least one selected from a 1/2 hydrate, 1 hydrate, and3/2 hydrate; the first component is the sole pharmaceutical activeingredient contained in the preparation; the second component istyloxapol and is present in said liquid preparation in an amountsufficient to stabilize said first component; and wherein said stableliquid preparation is formulated for ophthalmic administration.
 2. Theaqueous liquid preparation according to claim 1, further comprising aquaternary ammonium salt.
 3. The aqueous liquid preparation according toclaim 1, wherein the first component is a2-amino-3-(4-bromobenzoyl)phenylacetic acid sodium salt.
 4. The aqueousliquid preparation according to claim 1, wherein the concentration oftyloxapol is from about 0.01 w/v % to about 0.05 w/v %; and wherein thefirst component is a 2-amino-3-(4-bromobenzoyl)phenylacetic acid sodiumsalt, wherein the concentration of the2-amino-3-(4-bromobenzoyl)phenylacetic acid sodium salt is from about0.01 to about 0.2 w/v %.
 5. The aqueous liquid preparation according toclaim 4, wherein the concentration of the2-amino-3-(4-bromobenzoyl)phenylacetic acid sodium salt is about 0.1 w/v%.
 6. The aqueous liquid preparation according to claim 1, wherein thepH is from about 7.5 to about 8.5.
 7. The stable aqueous liquidpreparation of claim 1, wherein the stable aqueous liquid preparationconsists essentially of: (a) 2-amino-3-(4-bromobenzoyl)phenylacetic acidsodium salt, (b) tyloxapol, (c) boric acid, (d) sodium tetraborate, (e)EDTA sodium salt, (f) benzalkonium chloride, (g) polyvinylpyrrolidone,and (h) sodium sulfite, wherein said liquid preparation is formulatedfor ophthalmic administration, and wherein the concentration of the2-amino-3-(4-bromobenzoyl)phenylacetic acid sodium salt is from about0.02 w/v % to about 0.1 w/v %.
 8. A stable aqueous liquid preparationcomprising: (a) a first component; and (b) a second component; whereinthe first component is 2-amino-3-(4-bromobenzoyl)phenylacetic acid or apharmacologically acceptable salt thereof or a hydrate thereof, whereinthe hydrate is at least one selected from a 1/2 hydrate, 1 hydrate, and3/2 hydrate the first component is the sole pharmaceutical activeingredient contained in the preparation; the second component istyloxapol; wherein said stable liquid preparation is formulated forophthalmic administration; and wherein the stable aqueous liquidpreparation is characterized in that greater than about 90% of theoriginal amount of the first component remains in the preparation afterstorage at about 60° C. for 4 weeks.
 9. The aqueous liquid preparationaccording to claim 8, further comprising a quaternary ammonium salt. 10.The stable aqueous liquid preparation of claim 8, wherein the stableaqueous liquid preparation is characterized in that greater than about92% of the original amount of the first component remains in thepreparation after storage at about 60° C. for 4 weeks.
 11. The aqueousliquid preparation according to claim 8, wherein the concentration oftyloxapol is from about 0.01 w/v % to about 0.05 w/v %; and wherein thefirst component is a 2-amino-3-(4-bromobenzoyl)phenylacetic acid sodiumsalt, wherein the concentration of the2-amino-3-(4-bromobenzoyl)phenylacetic acid sodium salt is from about0.01 to about 0.2 w/v %.
 12. The aqueous liquid preparation according toclaim 11, wherein the pH is from about 7.5 to about 8.5.
 13. The stableaqueous liquid preparation of claim 8, wherein the stable aqueous liquidpreparation consists essentially of: (a)2-amino-3-(4-bromobenzoyl)phenylacetic acid or a pharmacologicallyacceptable salt thereof or a hydrate thereof, wherein the hydrate is atleast one selected from a 1/2 hydrate, 1 hydrate, and 3/2 hydrate; (b)tyloxapol; (c) boric acid; (d) sodium tetraborate; (e) EDTA sodium salt;(f) benzalkonium chloride; (g) polyvinylpyrrolidone; and (h) sodiumsulfite; and wherein the concentration of the2-amino-3-(4-bromobenzoyl)phenylacetic acid sodium salt is from about0.02 w/v % to about 0.1 w/v %.
 14. A stable aqueous liquid preparationcomprising: (a) a first component; and (b) a second component; whereinthe first component is 2-amino-3-(4-bromobenzoyl)phenylacetic acid or apharmacologically acceptable salt thereof or a hydrate thereof, whereinthe hydrate is at least one selected from a 1/2 hydrate, 1 hydrate, and3/2 hydrate; the first component is the sole pharmaceutical activeingredient contained in the preparation; the second component istyloxapol; wherein said stable liquid preparation is formulated forophthalmic administration; provided that the liquid preparation does notinclude mannitol.
 15. The aqueous liquid preparation according to claim14, further comprising a quaternary ammonium salt.
 16. The aqueousliquid preparation according to claim 14, wherein the first component isa 2-amino-3-(4-bromobenzoyl)phenylacetic acid sodium salt.
 17. Theaqueous liquid preparation according to claim 16, wherein theconcentration of tyloxapol is from about 0.01 w/v % to about 0.05 w/v %and the concentration of the 2-amino-3-(4-bromobenzoyl)phenylacetic acidsodium salt is from about 0.05 to about 0.2 w/v %.
 18. The aqueousliquid preparation according to claim 17, wherein the pH is from about7.5 to about 8.5.
 19. The stable aqueous liquid preparation of claim 14;wherein the stable aqueous liquid preparation consists essentially of:(a) 2-amino-3-(4-bromobenzoyl)phenylacetic acid or a pharmacologicallyacceptable salt thereof or a hydrate thereof, wherein the hydrate is atleast one selected from a 1/2 hydrate, 1 hydrate, and 3/2 hydrate; (b)tyloxapol; (c) boric acid; (d) sodium tetraborate; (e) EDTA sodium salt;(f) benzalkonium chloride; (g) polyvinylpyrrolidone; and (h) sodiumsulfite; wherein the concentration of the2-amino-3-(4-bromobenzoyl)phenylacetic acid sodium salt is from about0.02 w/v % to about 0.1 w/v %.
 20. The stable aqueous liquid preparationof claim 14, wherein the stable aqueous liquid preparation ischaracterized in that greater than about 90% of the original amount ofthe first component remains in the preparation after storage at about60° C. for 4 weeks.
 21. The aqueous liquid preparation according toclaim 20, further comprising a quaternary ammonium salt.
 22. The stableaqueous liquid preparation of claim 20; wherein the stable aqueousliquid preparation is characterized in that greater than about 92% ofthe original amount of the first component remains in the preparationafter storage at about 60° C. for 4 weeks.
 23. The aqueous liquidpreparation according to claim 20, wherein the concentration oftyloxapol is from about 0.01 w/v % to about 0.05 w/v %; and wherein thefirst component is a 2-amino-3-(4-bromobenzoyl)phenylacetic acid sodiumsalt, wherein the concentration of the2-amino-3-(4-bromobenzoyl)phenylacetic acid sodium salt is from about0.01 to about 0.2 w/v %.
 24. The aqueous liquid preparation according toclaim 23, wherein the pH is from about 7.5 to about 8.5.
 25. The stableaqueous liquid preparation of claim 20, wherein the stable aqueousliquid preparation consists essentially of: (a)2-amino-3-(4-bromobenzoyl)phenylacetic acid or a pharmacologicallyacceptable salt thereof or a hydrate thereof, wherein the hydrate is atleast one selected from a 1/2 hydrate, 1 hydrate, and 3/2 hydrate; (b)tyloxapol; (c) boric acid; (d) sodium tetraborate; (e) EDTA sodium salt;(f) benzalkonium chloride; (g) polyvinylpyrrolidone; and (h) sodiumsulfite; wherein said liquid preparation is formulated for ophthalmicadministration; and wherein the concentration of the2-amino-3-(4-bromobenzoyl)phenylacetic acid sodium salt is from about0.02 w/v % to about 0.1 w/v %.
 26. The aqueous liquid preparation ofclaim 1, wherein the aqueous liquid preparation further satisfies thepreservative efficacy standard of EP-criteria B of the EuropeanPharmacopoeia as follows: viable cell counts of bacteria (S. aureus, P.aeruginosa) 24 hours and 7 days after inoculation decrease to not morethan 1/10 and not more than 1/1000, respectively, and thereafter, thecell count levels off or decreases; and viable cell count of fungi (C.albicans, A. niger) 14 days after inoculation decreases to not more than1/10, and thereafter, the cell count keeps the same level as that of 14days after inoculation.
 27. The aqueous liquid preparation of claim 8,wherein the aqueous liquid preparation further satisfies thepreservative efficacy standard of EP-criteria B of the EuropeanPharmacopoeia as follows: viable cell counts of bacteria (S. aureus, P.aeruginosa) 24 hours and 7 days after inoculation decrease to not morethan 1/10 and not more than 1/1000, respectively, and thereafter, thecell count levels off or decreases; and viable cell count of fungi (C.albicans, A. niger) 14 days after inoculation decreases to not more than1/10, and thereafter, the cell count keeps the same level as that of 14days after inoculation.
 28. The aqueous liquid preparation of claim 14,wherein the aqueous liquid preparation further satisfies thepreservative efficacy standard of EP-criteria B of the EuropeanPharmacopoeia as follows: viable cell counts of bacteria (S. aureus, P.aeruginosa) 24 hours and 7 days after inoculation decrease to not morethan 1/10 and not more than 1/1000, respectively, and thereafter, thecell count levels off or decreases; and viable cell count of fungi (C.albicans, A. niger) 14 days after inoculation decreases to not more than1/10, and thereafter, the cell count keeps the same level as that of 14days after inoculation.
 29. The aqueous liquid preparation of claim 20,wherein the aqueous liquid preparation further satisfies thepreservative efficacy standard of EP-criteria B of the EuropeanPharmacopoeia as follows: viable cell counts of bacteria (S. aureus, P.aeruginosa) 24 hours and 7 days after inoculation decrease to not morethan 1/10 and not more than 1/1000, respectively, and thereafter, thecell count levels off or decreases; and viable cell count of fungi (C.albicans, A. niger) 14 days after inoculation decreases to not more than1/10, and thereafter, the cell count keeps the same level as that of 14days after inoculation.
 30. The aqueous liquid preparation of claim 22,wherein the aqueous liquid preparation further satisfies thepreservative efficacy standard of EP-criteria B of the EuropeanPharmacopoeia as follows: viable cell counts of bacteria (S. aureus, P.aeruginosa) 24 hours and 7 days after inoculation decrease to not morethan 1/10 and not more than 1/1000, respectively, and thereafter, thecell count levels off or decreases; and viable cell count of fungi (C.albicans, A. niger) 14 days after inoculation decreases to not more than1/10, and thereafter, the cell count keeps the same level as that of 14days after inoculation.